Objectives: To test the hypothesis that the thyroid gland of offspring of long-lived siblings is more resistant to stimulation with TSH compared to the thyroid gland of their partners, offspring and partners will receive a low dose of recombinant…
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Brief title
Condition
- Other condition
Synonym
Health condition
schildkliermetabolisme en weefselregeneratie in groepen die verschillen in familiaire langlevendheid
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome parameters of the study are the (precursor) hormones reflecting
the physiological response of the thyroid gland after TSH or T3 stimulation,
namely T3, T4, fT3, fT4, Tg and TSH. The levels of these hormones will be
compared between offspring of long-lived families and their partners.
Secondary outcome
Secondary outcome parameters of the study are processes potentially influenced
by thyroid metabolism, namely tissue regeneration, body temperature regulation,
heart rate and metabolomics.
Background summary
The Switchbox consortium demonstrated that offspring of long-lived families
display increased levels of TSH but similar levels of thyroid hormones (TH)
compared to their partners. Based on these findings, two hypotheses can be
formulated that will be tested in the THYRAGE (Resetting the THYRoid axis for
prevention of AGE-related diseases and co-morbidities) consortium. One
possibility is that the thyroid gland of offspring of long-lived siblings is
more resistant to stimulation with TSH compared to the thyroid gland of their
partners. An alternative explanation could be that the offspring show an
increased rate of TH clearance compared to their partners. As a result higher
TSH levels are required to increase the production of TH to ensure appropriate
circulating TH concentrations. The two hypotheses will be tested by performing
two challenge studies, one with recombinant human TSH (Thyrogen) and one with
synthetic T3 (Cytomel). In addition, offspring also displayed lower levels of
circulatory markers of bone turnover compared to their partners. Decreased bone
turnover could be reflective of a slower depletion of regenerative capacity, a
candidate mechanism contributing to longevity. It is unknown whether lower
levels of tissue regeneration are causally linked to enhanced TSH production
and/or increased TH clearance.
Study objective
Objectives: To test the hypothesis that the thyroid gland of offspring of
long-lived siblings is more resistant to stimulation with TSH compared to the
thyroid gland of their partners, offspring and partners will receive a low dose
of recombinant TSH.
To test the hypothesis that the offspring of long-lived siblings display an
increased rate of TH clearance from the circulation a T3 challenge will be
performed.
Secondary objectives: To determine whether there is a causative relationship
between changes of TH/TSH over time and changes in markers of tissue
regeneration and physiological parameters, markers of bone turnover will be
measured in blood and urine, immune signatures will be determined of
circulating peripheral mononuclear blood cells (PBMCs), and electrocardiography
(ECG), accelerometry and skin/core body temperature measurements will be
performed. In addition, biomaterial will be stored for additional future
measurements of biomarkers of thyroid hormone metabolism and/or tissue
regeneration.
Study design
Case-control intervention study.
Intervention
For the rhTSH challenge each participant will receive one intra-muscular
(musculus gluteus maximus) injection with a low dose of 0.1 mg (in 1 ml
solution) Thyrogen.
For the T3 challenge each participant will receive one oral dose of 100 µg
liothyronine (Cytomel).
Study burden and risks
During the rhTSH challenge we will administer a low dose of Thyrogen to healthy
subjects. In previous studies using the same Thyrogen dose only very minor
adverse events such as headache and nausea were observed. To assess the outcome
of this challenge, 14 blood samples will be collected during the first study
day. During the next three days one blood sample will be collected each day. In
addition to blood sampling, morning urine will be collected on each study day.
From study 1 onward, participants will wear an Equivital monitor to assess
physiological parameters for the duration of the study (4 days). Blood drawing,
collection of morning urine and wearing a physiological monitor are minimally
invasive procedures, consequently no direct benefits or risk associated with
study participation are expected.
During the T3 challenge we will administer one oral dose of Cytomel to healthy
subjects. Previous studies using the same dose of T3 showed no adverse effects
such as influences on general state of well-being or body weight. To assess the
outcome of this challenge, 25 blood samples will be collected during the first
study day. During the next four days one blood sample will be collected each
day. In addition to blood sampling, morning will be collected on each study
day. From study day 1 onward, participants will wear an Equivital monitor to
assess physiological parameters for the duration of the study (5 days). Blood
drawing, collection of morning urine and wearing a physiological monitor are
minimally invasive procedures, consequently no direct benefits or risk
associated with study participation are expected.
Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2
Leiden 2333ZA
NL
Listed location countries
Age
Inclusion criteria
Couples will be recruited from the Leiden Longevity Study (LLS), preferably from the 135 subjects that previously participated in the Switchbox phase 1 study, and preferably from the subgroup of 20 couples that were recruited for Group A (P11.116 * Switchbox). All subjects participating in Switchbox phase 1 were healthy, middle-aged (55-77 years) males or females with a BMI in the range of 22.5 kg/m2 to 33 kg/m2. Each couple participating in LLS consists of a child from a family enriched for longevity (case, offspring of long-lived sibling) and his/her current partner (control).
Exclusion criteria
* Cardiac arrhythmias
* (History of) thyroid diseases
* TSH hoger dan 4.0 mU/l
* fT4 level outside the normal range (9-24 pmol/l)
* Any significant chronic disease
* Renal, hepatic or endocrine disease
* Hormone therapy
* Difficulties to insert an intravenous cannula
* Recent participation in other research projects (within the last 3 months), participation in 2 or more projects in one year
* (History of) alcohol abuse (meer dan 28 units per week)
* Nicotine abuse
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-001497-15-NL |
| CCMO | NL57406.058.16 |